Clinical And Genetic Study On Pelizaeus-Merzbacher Disease And Pelizaeus-Merzbacher-like Disease

Pelizaeus-Merzbacher disease(PMD)is a rare x-linked recessive disorder presenting with nystagmus,impaired motor development,ataxia,and progressive spasticity.In the USA,the prevalence of PMD is estimated to be about 1/300,000 to 1/500,000.The main cause of PMD is alterations of the proteolipid protein 1(PLP1)gene.The PLP1 gene is located on chromosome Xq22.2.Duplication of the PLP1 gene is the most frequent gene defect,accounting for 50-70% of PMD cases,whereas point mutations in the coding sequence or affecting splice sites account for 10-25%of PMD cases.Pelizaeus-Merzbacher-like disease(PMLD)is an autosomal recessive syndrome characterized by early-onset nystagmus,delayed motor milestones,ataxia, progressive spasticity,partial seizures,mild peripheral neuropathy and diffuse leukodystrophy on MRI.It was caused by mutations in the GJA12 gene that encodes connexin 46.6.GJA12 gene was first mapped to 1q41 in 2004 and few of mutations were reported until now.Objectives The aims of present study were confirmed the clinical diagnosis and clarified the genotype-phenotype correlations in patients with PMD and PMLD by analyzing clinical data and changes of PLP1 gene and GJA12 gene.In addition genetic counseling and prenatal would been available for the family having probands using the results of this study.These datas collected from Peking University of First Hosipital.Methods 8 patients(male 8,female 1)and their parents as well as 14 family members of patient 2 were included in this study.Clinical data and DNA samples were collected from all the objects.Multiplex ligation-dependent probe amplification(MLPA)assays were performed to detect PLP1 duplication and the sequence analysis were used for alternations of PLP1 gene and GJA12 gene.These datas collected from Peking University of First Hosipital and these works all done at Peking University of First Hosipital.Results1.In 8 patients,they were diagnoses as three transitional,three classical,one connatal PMD and one PMLD according to the clinical and radiological criteria..2.PLP1 duplication was identified in patients 1-5 and their mothers were carriers.In P2' family,another 2 females(Ⅲ:3 andⅢ:4)with normal phenotype were proved to be carriers with PLPlduplication.A missense mutation in exon 4 of PLP1 gene[c.517C＞T(p.P173S)1 was found in patient 6 and his mother was carrier. 3.None change about PLP1 and GJA12 gene was found in patient 7.4.In patient P8,a c.216delGinsAA homozygous frameshift mutation was identified in exon 2 of GJA12 gene.Her father was heterozygote in this site,but her mother was normal. Moreover,uniparental disomy was found 1q in this patient and originated from her father through collaborated with the Clinical Genetic Service of Hong Kong.Conclusion1.The molecular diagnosis of PLP1 and GJA12 genes for PMD and PMLD patients has been set up in China,respectively.2.This is the first report to diagnosis PMD patients clinically and genetically in China,in which there were five using MLPA assay and one by DNA indirect sequencing.Three female carriers have been found in a four-generation family.3.One PMLD patient was diagnoses through analyzing GJA12 gene novel mutation and confirmed this mutation was uniparental disomy in 1 chromosome originated from her father. This is the first report in China.